CN112899321B - A method for preparing a key intermediate of lorlatinib - Google Patents
A method for preparing a key intermediate of lorlatinib Download PDFInfo
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Abstract
本发明提供了一种劳拉替尼关键中间体(式IV)的制备方法。具体地，本发明提供的制备方法包括步骤：(1)在含生物酶的生物酶催化还原体系中，使式I化合物进行还原反应，从而形成式II化合物；(2)在第一惰性溶剂中，在正丁基锂和二氧化碳的存在下，使步骤(1)制得的式Ⅱ化合物反应，从而得到式III化合物；和(3)在第二惰性溶剂中，使步骤(2)得到的式III化合发生酯化反应，从而得到式IV化合物。本发明的制备方法合成路线段、成本低、处理简单。The present invention provides a method for preparing a key intermediate of lorlatinib (Formula IV). Specifically, the preparation method provided by the present invention comprises the steps of: (1) subjecting a compound of Formula I to a reduction reaction in a bioenzyme catalytic reduction system containing a bioenzyme, thereby forming a compound of Formula II; (2) subjecting the compound of Formula II obtained in Step (1) to a reaction in the presence of n-butyl lithium and carbon dioxide in a first inert solvent, thereby obtaining a compound of Formula III; and (3) subjecting the compound of Formula III obtained in Step (2) to an esterification reaction in a second inert solvent, thereby obtaining a compound of Formula IV. The preparation method of the present invention has a short synthesis route, low cost, and simple processing.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a key intermediate 5-fluoro-3-methyl isobenzofuran-1 (3H) -one of Laratinib.
Background
Latifinib (Lorlatinib) is a potent inhibitor with dual ALK/ROSI and has an extremely important role in the treatment of cancer
Latification is developed by the American-type-trim company, and the ALK inhibitor modified by crizotinib (Crizotinib) enters a clinical stage in 2014, so that the Latification has remarkable curative effect on lung cancer.
5-Fluoro-3-methyl isobenzofuran-1 (3H) -one is used as an important intermediate for synthesis of loratidine, and has the advantages of long synthetic route, high cost, low yield and complex treatment in the prior report. .
In view of the foregoing, there is a strong need in the art to develop a novel synthetic route for 5-fluoro-3-methylisobenzofuran-1 (3H) -one that is short in route, simple to operate, high in yield, high in chiral purity, and extremely low in cost.
Disclosure of Invention
The invention aims to provide a novel synthetic route of 5-fluoro-3-methyl isobenzofuran-1 (3H) -one, which has the advantages of short route, simple and convenient operation, high yield, high chiral purity and extremely low cost.
In a first aspect of the present invention there is provided a process for the preparation of a compound of formula IV, the process comprising the steps of:
(1) In a biological enzyme catalytic reduction system containing biological enzyme, carrying out reduction reaction on the compound of the formula I, so as to form a compound of the formula II;
(2) Reacting the compound of formula II obtained in step (1) in a first inert solvent in the presence of n-butyllithium and carbon dioxide to obtain a compound of formula III, and
(3) And (3) in a second inert solvent, carrying out esterification reaction on the compound of the formula III obtained in the step (2), thereby obtaining the compound of the formula IV.
In another preferred embodiment, in step (1), the chiral purity of the compound of formula II is greater than 99.9%.
In another preferred embodiment, in step (3), the chiral purity of the compound of formula IV is greater than 99.9%.
In another preferred example, the reaction temperature in the step (2) is-80 to-30 ℃, preferably-60 to-30 ℃, and more preferably-40 to-30 ℃.
In another preferred embodiment, the molar ratio of n-butyllithium to formula II in step (2) is (0.8-1.2): 1, more preferably (1.+ -. 0.1): 1.
In another preferred embodiment, the molar ratio of n-butyllithium to formula II in the step (2) is (0.9-1.0): 1.
In another preferred embodiment, in step (2), the first inert solvent is an ether solvent, preferably a C2-C6 ether solvent, more preferably diethyl ether.
In another preferred embodiment, in step (2), the reaction time is 10 to 180 minutes, preferably 10 to 60 minutes, and most preferably 45 to 50 minutes.
In another preferred embodiment, step (2) includes the steps of:
(2.1) reacting the compound of formula II prepared in step (1) in the presence of n-butyllithium in a first inert solvent to obtain a reaction system comprising a compound of formula II substituted with n-butyllithium;
(2.2) introducing CO 2 into the reaction system containing the n-butyllithium substituted compound of formula II in the step (2.1) to react the n-butyllithium substituted compound of formula II, thereby obtaining the compound of formula III.
In another preferred embodiment, in the step (2.2), the flow rate of CO 2 is 3 to 8L/h per 100ml of the first inert solvent.
In another preferred embodiment, the reaction time of step (2.1) is 5 to 60min, preferably 20 to 40min.
In another preferred embodiment, the reaction time of step (2.2) is 5 to 50min, preferably 10 to 30min, more preferably 15 to 20min.
In another preferred embodiment, step (2) further comprises a second work-up step for isolating and/or purifying the compound of formula III.
In another preferred embodiment, the second post-treatment step comprises separating, removing solvent (preferably, removing solvent by distillation under reduced pressure) and/or drying (preferably, air-drying).
In another preferred embodiment, the second post-treatment step does not comprise chiral resolution and/or chromatographic separation.
In another preferred embodiment, in step (1), the biological enzyme is a combination of perakine reductase and coenzyme NADPH.
In another preferred embodiment, in step (1), the concentration of perakine reductase is 0.38-1.0mg/ml (preferably 0.62-0.85mg/ml; more preferably 0.69-0.77 mg/ml), based on the total volume of the bio-enzyme catalytic system.
In another preferred embodiment, in step (1), the final concentration of perakine reductase in the bio-enzyme catalytic reduction system is 0.38-1.0mg/ml (preferably 0.62-0.85mg/ml; more preferably 0.69-0.77 mg/ml).
In another preferred example, in step (1), the concentration of coenzyme NADPH is 0.002 to 0.15mmol/L (preferably, 0.005 to 0.05mmol/L; more preferably, 0.01 to 0.03mmol/L; most preferably, 0.01 to 0.02 mmol/L), based on the total volume of the bio-enzyme catalytic system.
In another preferred example, in the step (1), the final concentration of the coenzyme NADPH in the bio-enzyme catalytic reduction system is 0.002 to 0.15mmol/L (preferably, 0.005 to 0.05mmol/L; more preferably, 0.01 to 0.03mmol/L; most preferably, 0.01 to 0.02 mmol/L).
In another preferred embodiment, in the step (1), the mass ratio of glucose dehydrogenase to perakine reductase in the bio-enzyme catalytic system is (0.5-2): 1, preferably (1.+ -. 0.2): 1, more preferably (1.+ -. 0.1): 1.
In another preferred embodiment, in step (1), the pH of the bio-enzyme catalytic system is 7.+ -. 1 (preferably, 7.+ -. 0.5; more preferably, 7.+ -. 0.1).
In another preferred embodiment, in step (1), the concentration of the compound of formula I is from 0.1 to 2mM (mmol/L) (preferably from 0.3 to 1.0; more preferably from 0.5 to 0.7 mM), based on the total volume of the bio-enzyme catalytic system.
In another preferred embodiment, in step (1), the final concentration of the compound of formula I in the bio-enzyme catalytic reduction system is 0.1 to 2mM (preferably 0.3 to 1.0; more preferably 0.5 to 0.7 mM). In another preferred embodiment, in step (1), the bio-enzyme catalytic system further comprises glucose and glucose dehydrogenase.
In another preferred embodiment, in step (1), the concentration of glucose is 0.1 to 10mM (i.e., 0.0001 to 0.01 mmol/mL), preferably 0.5 to 2mM (i.e., 0.0005 to 0.002mmol/mL), more preferably 1.+ -. 0.1mM (0.001.+ -. 0.0001 mmol/mL)), based on the total volume of the bio-enzyme catalytic system.
In another preferred embodiment, in step (1), the concentration of glucose dehydrogenase is 0.38-1.0mg/ml (preferably, 0.62-0.85mg/ml; more preferably, 0.69-0.77 mg/ml), based on the total volume of the bio-enzyme catalytic system.
In another preferred embodiment, in step (1), the final concentration of glucose dehydrogenase in the bio-enzyme catalytic reduction system is 0.38-1.0mg/ml (preferably, 0.62-0.85mg/ml; more preferably, 0.69-0.77 mg/ml).
In another preferred embodiment, the solvent of the bio-enzyme catalytic system of step (1) is water.
In another preferred embodiment, the bio-enzyme catalytic system further comprises a pH buffer system.
In another preferred embodiment, the pH buffer system is kpi buffer system.
In another preferred embodiment, the bio-enzyme catalytic system consists essentially of the compound of formula I, perakine reductase, glucose dehydrogenase, glucose, NADPH, water and a pH buffer system (preferably, kpi buffer system).
In another preferred embodiment, step (1) further comprises a first work-up step for isolating and/or purifying the compound of formula II.
In another preferred embodiment, in step (1), the first post-treatment step comprises extraction of the liquid fraction, and/or removal of the solvent (preferably, removal of the solvent by concentration under reduced pressure).
In another preferred embodiment, in step (1), the first post-treatment step does not comprise chiral resolution and/or chromatographic separation.
In another preferred embodiment, in step (3), the esterification reaction is carried out in the presence of an acid.
In another preferred embodiment, in step (3), the acid is selected from the group consisting of sulfuric acid, acetic acid, oxalic acid, phosphoric acid, or a combination thereof, preferably the acid is selected from the group consisting of phosphoric acid, sulfuric acid, or a combination thereof, more preferably the acid is sulfuric acid.
In another preferred embodiment, in step (3), the second inert solvent is selected from the group consisting of an alcoholic solvent, water, or a combination thereof.
In another preferred embodiment, in the step (3), the second inert solvent is a mixed solvent composed of an alcohol solvent and water;
In another preferred embodiment, in the step (3), the alcoholic solvent is selected from the group consisting of methanol, ethanol, and a combination thereof, and preferably, the alcoholic solvent is ethanol (absolute ethanol).
In another preferred embodiment, in the step (3), the second inert solvent is a mixed solvent composed of an alcohol solvent selected from methanol, ethanol, or a combination thereof and water, and most preferably, a mixed solvent composed of ethanol and water.
In another preferred embodiment, in the step (3), the volume ratio of the alcohol solvent to water in the second inert solvent is (5 to 20): 1, more preferably (9±1): 1.
In another preferred embodiment, in the step (3), the volume ratio of ethanol (absolute ethanol) to water in the second inert solvent is (5-20): 1, more preferably, (9±1): 1.
In another preferred embodiment, in step (3), the volume to mass ratio (ml: g) of the second inert solvent to the compound of formula III is (5 to 20): 1, more preferably (10.+ -. 2): 1, most preferably (10.+ -. 1): 1.
In another preferred embodiment, in the step (3), the molar ratio of the acid to the compound of formula III is (5-20): 1, preferably (10+ -1): 1;
In another preferred embodiment, in the step (3), the reaction temperature of the esterification reaction is 0 to 50 ℃, preferably 20 to 30 ℃.
In another preferred embodiment, in the step (3), the reaction time of the esterification reaction is 1 to 10 hours, preferably 2 to 3 hours.
In another preferred embodiment, step (3) further comprises a third work-up step for isolating and/or purifying the compound of formula IV.
In another preferred embodiment, the third post-treatment comprises extractive fractionation and/or solvent removal (preferably, solvent removal by pressure distillation).
In another preferred embodiment, the third work-up step does not comprise chiral resolution and/or chromatographic separation.
In another preferred embodiment, the preparation method does not comprise a chiral resolution treatment step.
In another preferred embodiment, the preparation method does not include chromatographic separation.
In another preferred embodiment, the preparation method comprises only a simple post-treatment step.
In another preferred embodiment, the overall yield of the preparation method is not less than 70%, more preferably not less than 75%.
In another preferred embodiment, the purity of the compound of formula IV prepared by the preparation method is more than or equal to 98%, preferably more than or equal to 99.5%.
In a second aspect of the invention, there is provided an intermediate of formula IV,
The intermediate is prepared by the preparation method according to the first aspect.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 is a chromatogram showing the chiral purity of the product of example 1.
FIG. 2 is a chromatogram showing the chiral purity of the product of example 2.
FIG. 3 is a chromatogram showing the chiral purity of the product of example 3.
FIG. 4 is a chromatogram showing the purity of the product of example 7.
FIG. 5 is a chromatogram showing the purity of the product of example 8.
Detailed Description
The inventors have studied extensively and intensively and have surprisingly found that bio-enzyme catalysis is very suitable for chiral reduction of compounds of formula I. Furthermore, the inventors have unexpectedly found that n-butyllithium and carbon dioxide are particularly suitable for carboxylating compounds of formula II, compared to other conventional carboxylation systems (such as palladium acetate and carbon monoxide systems), to obtain compounds of formula III in high yields of more than 80% and in reaction times of less than 1 hour. The inventor provides a new preparation method (or synthetic route) for directly preparing the 5-fluoro-3-methyl isobenzofuran-1 (3H) -one (formula IV) with high purity and chiral purity by taking 2-bromo-5-fluoro acetophenone (formula I) as a raw material through three steps of reactions for the first time. The present invention has been completed based on this inventor.
Terminology
"Work-up" refers to a step for separating and/or purifying (purifying) a target compound from a reaction system containing the target compound, unless otherwise specified. As used herein, "simple work-up" refers to a step of separating and/or purifying (purifying) a target compound from a reaction system containing the target compound by a usual and industrially applicable work-up means (method or process), for example, by one or more of liquid separation, extraction, drying, distillation, concentration, filtration, drying, crystallization, etc., and generally, simple work-up does not include chiral resolution, chromatographic separation, etc.
As used herein perakine reductase (Perakine Reductase), also known as serpentine root perakine reductase, is derived from the medicinal plant serpentine root wood of the genus rauvolfia of the family oleander.
Preparation method of loratidine key intermediate (formula IV)
The invention provides a new synthesis route of the intermediate shown in the formula IV, and the synthesis route (or method) greatly shortens the synthesis method provided by the original report, simplifies the operation, improves the yield and greatly reduces the cost. More importantly, the method of racemization resolution by a chemical method used in the prior resolution is changed, and biological enzyme is adopted as a catalyst, so that the method is environment-friendly, simple and convenient, high in yield, free of side reaction and greatly improved in product quality.
Typically, the present invention provides a process for the preparation of a compound of formula IV, the process comprising the steps of:
(1) The chiral reduction of the formula I is carried out under the catalysis of biological enzyme to obtain the chiral formula II
Preferably, the biological enzyme is perakine reductase, and the coenzyme NADPH.
In a specific embodiment, step (1) comprises the steps of providing a mixture of the compound of formula I, a biological enzyme (perakine reductase and glucose dehydrogenase) in a solvent (preferably, the solvent is water), adding a buffer, and optionally glucose and NADPH, to the mixture, thereby obtaining a biological enzyme catalytic reduction system, and allowing the compound of formula I to form the compound of formula II in the biological enzyme catalytic reduction system.
Preferably, the concentration of the biological enzyme perakine in the mixture is 0.5-1.3mg/ml, preferably 0.8-1.1mg/ml, most preferably 0.9-1.0mg/ml.
Preferably, the concentration of the compound of formula I in the mixture is 0.13 to 2.6, preferably 0.4 to 1.3mM, more preferably 0.65 to 0.9mM.
Preferably, the buffer is Kpi buffer with Ph of 7±0.5.
Preferably, the buffer is a 50+ -10 nM Kpi buffer.
Preferably, the volume ratio of buffer to the mixture is (0.1-0.5): 1, preferably 0.3+ -0.1:1.
In another preferred embodiment, step (1) further comprises a step (i.e., a first post-treatment step) of adding an organic solvent such as ethyl acetate to the system containing the compound of formula II, and concentrating under reduced pressure to remove the organic solvent, thereby obtaining the isolated compound of formula II.
In another preferred embodiment, in the step (1), the solvent is water.
In a specific embodiment, the method of preparing a compound of formula IV further comprises the steps of:
(2) Reacting the compound of formula II obtained in step (1) in the presence of n-butyllithium and carbon dioxide in a first inert solvent to obtain a compound of formula III, preferably, reacting the compound of formula II with carbon dioxide after electrophilic substitution of n-butyllithium to produce a compound of formula III;
in another preferred embodiment, in the step (2), the reaction temperature of the reaction is-80 to-30 ℃, preferably-60 to-30 ℃, and most preferably-40 to-30 ℃
In another preferred embodiment, in the step (2), the molar ratio of n-butyllithium to the compound of formula II is (0.8-1.2): 1, most preferably (1.+ -. 0.1): 1.
In another preferred example, the step (2) comprises the steps of (2.1) providing a solution of the compound of formula II in a first inert solvent, cooling to-40 to-38 ℃, adding (preferably dropwise) n-butyllithium (preferably, n-butyllithium is added in the form of an n-hexane solution thereof), and (2.2) introducing CO 2 to carry out bubbling reaction for 15-20 min, thereby obtaining a reaction solution containing the compound of formula III.
Preferably, the flow rate of CO 2 is 3 to 8L/h per 100ml of the first inert solvent.
In another preferred embodiment, the reaction in step (2) is carried out at a pressure of 5 atm or less, and preferably, the reaction in step (2) is carried out at normal pressure (0.9 to 1.1 atm).
In another preferred embodiment, step (2) further comprises a step (i.e., a second post-treatment step) of adding the reaction solution containing the compound of formula III to a dilute hydrochloric acid solution (e.g., a 1.2M dilute hydrochloric acid solution), stirring (e.g., for 30 minutes), removing the organic layer, removing the solvent, and/or drying to obtain the compound of formula III.
In a specific embodiment, the method of preparing a compound of formula IV further comprises the steps of:
(3) Subjecting the compound of formula III to an esterification reaction to obtain the compound of formula IV.
In another preferred embodiment, in the step (3), the esterification reaction is performed in the presence of an acid.
In another preferred embodiment, in the step (3), the esterification reaction is performed in the presence of one or more of sulfuric acid, acetic acid, oxalic acid, and phosphoric acid (preferably, phosphoric acid, sulfuric acid, or a combination thereof; most preferably, sulfuric acid).
In another preferred example, in the step (3), the solvent (i.e., the second inert solvent) for the esterification reaction is a mixed solvent formed by one or a combination of methanol, ethanol, or other polyols and water, preferably a mixed solvent formed by methanol, ethanol, or a combination thereof and water, and most preferably a mixed solvent formed by ethanol and water.
In another preferred embodiment, step (3) comprises the steps of providing a solution of the compound of formula III in a second inert solvent, adding phosphoric acid and reacting (preferably at 20-30 ℃) for 2-3 hours to obtain the compound of formula IV.
In another preferred embodiment, step (3) further comprises the step (i.e. a third treatment step) of adding the reaction droplets to water, extracting the separated liquid by an organic solvent (e.g. dichloromethane), taking the organic layer, and removing the organic solvent (preferably by pressure distillation), thereby obtaining the isolated and/or purified compound of formula IV.
The main advantages of the invention include:
(a) The synthesis method provided by the original report is greatly shortened, and the key intermediate 5-fluoro-3-methyl isobenzofuran-1 (3H) -one (formula IV) can be prepared from 2-bromo-5-fluoro acetophenone (formula I) serving as a raw material by only three steps.
(B) The preparation method of the invention is simple to operate. Each step does not need to carry out complicated operations such as chromatographic separation, chiral resolution and the like.
(C) The compound of the formula IV obtained by the preparation method has high purity (> 98%) and chiral purity (even up to 100%).
(D) The total yield of the preparation method of the invention can reach 77.1 percent.
(E) Avoiding the racemization resolution of the traditional chemical method used for chiral resolution and adopting a method of taking biological enzyme as a catalyst.
(F) Greatly reduces the cost and avoids the use of expensive chromatographic separation, chiral resolution and other operations.
(G) Environmental protection, simplicity and convenience, no side reaction, and greatly improved product quality.
(H) The preparation method does not need high-pressure conditions.
In particular, when a mixed solvent of absolute ethanol and water is used as the inert solvent for the reaction of step (3) and in the presence of sulfuric acid, the purity of the key intermediate of loratidine produced by the process of the present invention may even reach 99.8%.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Unless otherwise indicated, reagents, starting materials, catalysts, enzymes and the like used in the examples may be obtained commercially or prepared by conventional methods, e.g., perakine reductase used in the examples is available from Shanghai Runtai pharmaceutical sciences, inc., and the compounds of formula I may be obtained commercially.
EXAMPLE 1 preparation of Compounds of formula II
The compound of formula I (18.0 mg,0.083mmol, commercially available) was added to water (100 mL), perakine reductase (100 mg), glucose dehydrogenase (100 mg), 50mM Kpi buffer (30 mL) with Ph of 7, glucose (0.03 g, 0.13 mmol), NADPH (1.48 mg, 0.002 mmol) 20-30℃were added and stirred for about 10h, ethyl acetate (50 mL) extract was added, ethyl acetate (30 mL) extract was added, ethyl acetate was combined, and the solvent was concentrated under reduced pressure to give a pale yellow solid 16.53mg yield 91.0% (relative to formula I). MS (ESI) [ m+1] + = 220.20. The chiral purity was 100.0% as detected (see FIG. 1).
EXAMPLE 2 preparation of Compounds of formula II
The compound of formula I (18.0 mg,0.083mmol, commercially available) was added to water (100 mL), perakine reductase (110 mg), glucose dehydrogenase (100 mg), 50mM Kpi buffer (30 mL) with Ph of 7, glucose (0.03 g, 0.13 mmol), NADPH (1.48 mg, 0.002 mmol) 20-30℃were added and stirred for about 10h, ethyl acetate (50 mL) extract was added, ethyl acetate (30 mL) extract was added, ethyl acetate was combined, and the solvent was concentrated under reduced pressure to give a pale yellow solid 15.63mg yield 86.1% (relative to formula I). MS (ESI) [ m+1] + = 220.20. The chiral purity was 99.7% (see FIG. 2).
EXAMPLE 3 preparation of Compounds of formula II
The compound of formula I (18.0 mg,0.083mmol, commercially available) was added to water (100 mL), perakine reductase (70 mg), glucose dehydrogenase (100 mg), 50mM Kpi buffer (30 mL) with Ph of 7, glucose (0.03 g, 0.13 mmol), NADPH (1.48 mg, 0.002 mmol) 20-30℃were added and stirred for about 10h, ethyl acetate (50 mL) extract was added, ethyl acetate (30 mL) extract was added, ethyl acetate was combined, and the solvent was concentrated under reduced pressure to give a pale yellow solid 14.91mg yield 82.0% (relative to formula I). MS (ESI) [ M+1] + =220.2. The chiral purity was 97.3% as detected (see FIG. 3).
EXAMPLE 4 preparation of Compounds of formula III
The compound of formula II (10 g,45.6mmol, prepared as in example 1) was added to diethyl ether (100 ml), ethanol dry ice was cooled to-40 ℃ to-38 ℃, 1.6M n-butyllithium n-hexane solution (28 ml45 mmol) was added dropwise, wen Di was kept at no more than-30 ℃, stirring was carried out for 30min after completion of the dropwise addition, CO 2 was introduced at-30 ℃ for bubbling reaction for 15-20min, cooling was removed, heating was slowly carried out to about 20 ℃, the reaction solution was added dropwise to 1.2M dilute hydrochloric acid solution (100 ml), stirring was carried out for 30min, the organic layer was separated by standing, dried over anhydrous sodium sulfate, anhydrous sodium sulfate was removed by filtration, a pale yellow solid was obtained by distillation under reduced pressure at 30 ℃, and 50 ℃ was dried by air blast, to obtain a pale yellow solid (7.99 g) in 95.1% yield (relative to formula II) MS (ESI) [ M+1] + =35.
EXAMPLE 5 preparation of Compounds of formula III
The compound of formula II (10 g,45.6mmol, prepared as in example 1) was added to diethyl ether (100 ml), ethanol dry ice was cooled to-40 ℃ to-38 ℃, 1.6M n-butyllithium n-hexane solution (22.5 ml36 mmol) was added dropwise, wen Di addition was kept at no more than-30 ℃, stirring was carried out for 30min after completion of the dropwise addition, CO 2 was introduced at-30 ℃ for bubbling reaction for 15-20min, cooling was withdrawn, heating was slowly carried out to about 20 ℃, the reaction solution was added dropwise to 1.2M dilute hydrochloric acid solution (100 ml), stirring was carried out for 30min, the organic layer was separated by standing, dried over anhydrous sodium sulfate, anhydrous sodium sulfate was removed by filtration, a pale yellow solid was obtained by distillation under reduced pressure at 50 ℃, and blast drying was obtained as a pale yellow solid (6.93 g) in 82.5% (relative to formula II) MS (ESI) [ M+1] + = 185.16).
EXAMPLE 6 preparation of Compounds of formula III
The compound of formula II (10 g,45.6mmol, prepared as in example 1) was added to diethyl ether (100 ml), ethanol dry ice was cooled to-40 ℃ to-38 ℃, 1.6M n-butyllithium n-hexane solution (33.8 ml54 mmol) was added dropwise, wen Di addition was kept at no more than-30 ℃, stirring was carried out for 30min after completion of the dropwise addition, CO 2 was introduced at-30 ℃ for 15-20min of bubbling reaction, cooling was withdrawn, heating was slowly carried out to about 20 ℃, the reaction solution was added dropwise to 1.2M dilute hydrochloric acid solution (100 ml), stirring was carried out for 30min, the organic layer was separated by standing, dried over anhydrous sodium sulfate, anhydrous sodium sulfate was removed by filtration, distillation was carried out under reduced pressure at 30 ℃ to give a pale yellow solid, 50 ℃ air blast was dried, and a pale yellow solid (7.11 g) was obtained in 84.6% (relative to formula II) MS (ESI) [ M+1] + = 185.16.
EXAMPLE 7 preparation of Compounds of formula IV
The compound of formula III (50 g,0.27mol, prepared as described in example 4) was added to a mixed solution of absolute ethanol (450 ml) and water (50 ml), concentrated sulfuric acid (264.6 g, 2.7 mol) was added dropwise, the reaction was completed at 20-30℃for 2-3 hours, the reaction solution was added dropwise to water (600 ml), stirred, extracted with methylene chloride (400 ml), and then extracted with methylene chloride (200 ml), the methylene chloride was combined and pressure distilled to give the product (40.14 g) in 89.1% (relative to formula III) MS (ESI) [ M+1] + = 167.17). The purity was 99.8% (see fig. 4) as tested.
EXAMPLE 8 preparation of Compounds of formula IV
A compound of formula III (50 g,0.27mol, prepared as described in example 4) was added to a mixed solution of methanol (450 ml) and water (50 ml), phosphoric acid (264.6 g, 2.7 mol) was added dropwise, the temperature was controlled at 20-30℃and the addition was completed, the reaction was carried out for 2-3 hours, the reaction solution was added dropwise to water (600 ml), stirred, extracted with methylene chloride (400 ml), and then extracted with methylene chloride (200 ml), the methylene chloride was combined and distilled under pressure to give a product (39.3 g) in a yield of 87.2% (relative to formula III) MS (ESI) [ M+1] + = 167.17. The purity was found to be 98.9% (see fig. 5).
Comparative example 1 preparation of Compounds of formula III
The compound of formula II (10 g,45.6mmol, prepared as in example 1) was added to ethanol (600 ml), palladium acetate (8.0 g) was added to the autoclave, carbon monoxide was introduced after displacing the air in the autoclave, the air pressure in the autoclave was maintained at 12atm, the temperature was raised to 110 ℃, the reaction was allowed to proceed for 6h, the temperature was lowered to room temperature, the solid catalyst was removed by filtration, the filtrate was concentrated under reduced pressure to give a brown solid compound, which was dried by air blow at 50℃to give a earthy yellow solid (4.12 g, yield: 49.0%) (MS (ESI): [ m+1] + = 185.16).
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
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